Rational design of microRNA-responsive switch for programmable translational control in mammalian cells

Hui Ning, Gan Liu, Lei Li, Qiang Liu, Huiya Huang and Zhen Xie ()
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Hui Ning: Tsinghua University
Gan Liu: Syngentech Inc., Zhongguancun Life Science Park, Changping District
Lei Li: Tsinghua University
Qiang Liu: Syngentech Inc., Zhongguancun Life Science Park, Changping District
Huiya Huang: Syngentech Inc., Zhongguancun Life Science Park, Changping District
Zhen Xie: Tsinghua University

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Artificial RNA translation modulation usually relies on multiple components, such as RNA binding proteins (RBPs) or microRNAs (miRNAs) for off-switches and double-inverter cascades for on-switches. Recently, translational circular RNAs (circRNAs) were developed as promising alternatives for linear messenger RNAs (mRNAs). However, circRNAs still lack straightforward and programmable translation control strategies. Here, we rationally design a programmable miRNA-responsive internal ribosome entry site (IRES) translation activation and repression (PROMITAR) platform capable of implementing miRNA-based translation upregulation and downregulation in a single RNA construct. Based on the PROMITAR platform, we construct logic gates and cell-type classifier circRNAs and successfully identify desired mammalian cell types. We also demonstrate the potential therapeutic application of our platform for targeted cancer cell killing by encoding a cytotoxic protein in our engineered circRNAs. We expect our platform to expand the toolbox for RNA synthetic biology and provide an approach for potential biomedical applications in the future.

Date: 2023
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DOI: 10.1038/s41467-023-43065-w

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